RETROVIRAL IMMUNOTOXINS FOR LEUKEMIA

描述：（申请人摘要）免疫毒素（IT）是实验性的 通过连接抗体或细胞因子而制备的药物制剂， 特异性地与癌细胞结合到强效催化毒素上， 分子可以杀死细胞。主要目的是选择性地提供治疗 而不是像常规化疗那样直接作用于非靶器官。 尽管这些药剂选择性地结合并杀死癌细胞，但在临床上， 由于未能充分渗透和定位， 2）在非靶器官中的定位 限制了耐受剂量并使治疗窗收缩。在这 申请人将探索解决这一问题的办法。细胞 免疫系统如T细胞是最主要的细胞类型， 渗透，攻击和破坏癌细胞，并自然适合于 响应抗原攻击的细胞因子的表达和产生。 因此，他建议使用T细胞来传递逆转录病毒IT（retIT）。 由IL-4与基因修饰的白喉毒素在 白血病细胞。他已经建立了一个模型的retIT治疗，他将 作为将来尝试修改和改进RETIT的基础。他将 测试retIT治疗髓性白血病的有效性， 成人型白血病在该模型中，申请人生产了抗原 用辐射小鼠超免疫法建立特异性CTL细胞系T15 髓系白血病C1498。当用编码IL-4的逆转录病毒转导T15时， 剪接到截短的DT，T15细胞已显示表达和分泌IL-4 retIT特异性杀死IL-4R + C1498细胞，但不杀死IL-4R-细胞。 体外更重要的是，给予C1498肿瘤的小鼠显示出显著增强的 当用转导的T15细胞处理时的抗C1498作用与 对照在本申请的第一个目的中，申请人打算使用 该模型首先回答了关于IL-4 IT作用的重要问题， 和T15 CTL。IL-4IT的分泌是必需的吗 需要分泌多少才能达到抗癌效果那么， 分泌的retIT与抗癌效果的大小相关吗？是什么 CTL载体在retIT反应中的作用？我们能增强分泌， CTL交付retIT？在第二个目标中，他将决定是否重新分配 与传统的IT管理相比， 关于其对非靶器官系统的毒性作用和对 免疫反应凭借他已经确定的抗C1498效应， 一个基线，在最后一个目标，他会问是否重要的基因， 修改可以改善retit。

DESCRIPTION: (Applicant's Abstract) Immunotoxins (IT) are experimental pharmacologic agents that are made by linking antibodies or cytokines that specifically bind to cancer cells to potent catalytic toxins of which a single molecule can kill a cell. The major purpose is to deliver therapy selectively to cancer cells instead of nontarget organs as does conventional chemotherapy. Although these agents selectively bind and kill cancer cells, clinically they have been limited by their 1) failure to penetrate and localize in adequate concentrations in cancer target tissue 2) localization in nontarget organs limiting the tolerated dose and collapsing the therapeutic window. In this application, the applicant will explore a solution to this problem. Cells of the immune system such as T cells are the most prominent cell types that penetrate, attack, and destroy cancer cells and are naturally suited for the expression and production of cytokines in response to antigenic challenge. Therefore, he proposes using T cells to deliver retroviral IT (retIT) consisting of IL-4 spliced to genetically modified diphtheria toxin at the site of the leukemia cells. He has established a model of retIT therapy that he will use as a foundation for future attempts to modify and improve retIT. He will test the usefulness of retIT for therapy of myeloid leukemia, the most common adult form of leukemia. In this model, the applicant has produced an antigen specific CTL cell line called T15 by hyperimmunization with irradiated murine myeloid leukemia C1498. When T15 is transduced with retrovirus encoding IL-4 spliced to truncated DT, T15 cells have been shown to express and secrete IL-4 retIT which specifically kills IL-4R+ C1498 cells, but not IL-4R- cells in vitro. More importantly, mice given C1498 tumors show significantly enhanced anti-C1498 effects when treated with transduced T15 cells as compared to controls. In this application in the first aim, the applicant intends to use this model first to answer important questions regarding the role of IL-4 IT and T15 CTL in the first retroviral model. Is secretion of IL-4 IT necessary and how much must be secreted to get an anti-cancer effect? Does the amount of secreted retIT correlate with the magnitude of the anti-cancer effect? What is the role of the CTL vehicle in the retIT response? Can we enhance secretion and CTL delivery of retIT? In the second aim, he will determine if retIT administration has advantages over conventional IT administration particularly regarding their toxic effects on non-target organ systems and effects on the immune response. With the anti-C1498 effects that he has already established as a baseline, in the last aim he will ask whether or not important genetic modifications can improve retIT.